Our goal is to identify and characterize genes, pathways and molecular mechanisms that contribute to elevated IOP and glaucoma, This is a critical step for rationally improving the care of patients. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. The molecular mechanisms underlying IOP elevation and glaucoma are largely unidentified. We study the genetics of glaucoma using mouse models. Using mice to discover glaucoma pathways is an important approach as mice are experimentally tractable. (Aim 1) We will use the power of mouse genetics to identify genes and mechanism that induce IOP elevation in new glaucoma-relevant mutants that we have discovered and started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the molecular pathogenesis. We will collaborate to assess the human orthologs of the identified genes in human patients. (Aim 2) The limited availability of useful mutants remains a major factor hindering mechanistic discoveries. Thus, we will conduct a phenotype driven mutagenesis screen to identify novel genes and molecular mechanism involved in IOP elevation and glaucoma. We propose a sensitized ENU screen for glaucoma mutations. We have sensitized the screen in various ways including a mutation in the mouse ortholog of a human gene that predispose people to high IOP and glaucoma, a predisposition that we have repeated in mice. To hasten the discovery of mechanisms, we will complement genetics with state of the art sequencing and genomic approaches. Continuing to use the power of a phenotype-driven mutagenesis screen, in parallel with our proven experience in determining disease mechanisms and in examining ocular phenotypes, will enable us to identify and characterize new genets and molecular processes that contribute to elevated IOP and glaucoma. The new mutants will have great potential to transform our understanding of glaucoma.